Immune checkpoint modulators in early clinical development for the treatment of type 1 diabetes.

INTRODUCTION: Despite the improvements of insulin therapy, people with type 1 diabetes (T1D) still suffer from a decreased quality of life and life expectancy. The search toward a cure for T1D is therefore still a scorching open field of research. AREAS COVERED: Tackling the immune checkpoint signaling pathways has gained importance in the field of cancer immunotherapy. The same pathways can be targeted in autoimmunity with an opposite principle: to dampen the exaggerated immune response. In this review, we report a comprehensive excursus on the cellular and molecular mechanisms that lead to loss of immunological tolerance, and recent evidence on the role of immune checkpoint molecules in the development of T1D and their potential application for the mitigation of autoimmune diabetes. EXPERT OPINION: Contrasting results about the efficacy of immune checkpoint modulators for T1D have been published, with very few molecules from preclinical studies eligible for use in humans. The heterogeneous and complex pathophysiology of T1D may explain the conflicting evidence. Designing clinical trials that acknowledge the pathophysiological and clinical complexity of T1D and that forecast the need of simultaneously tackling different disease pathways will be crucial to enhance the benefits which may be gained by such compounds.

Central obesity, smoking habit, and hypertension are associated with lower antibody titres in response to COVID-19 mRNA vaccine.

AIMS: To explore variables associated with the serological response following COVID-19 mRNA vaccine. METHODS: Eighty-six healthcare workers adhering to the vaccination campaign against COVID-19 were enrolled in January-February 2021. All subjects underwent two COVID-19 mRNA vaccine inoculations (Pfizer/BioNTech) separated by 3 weeks. Blood samples were collected before the 1st and 1-4 weeks after the second inoculation. Clinical history, demographics, and vaccine side effects were recorded. Baseline anthropometric parameters were measured, and body composition was performed through dual-energy-X-ray absorptiometry. RESULTS: Higher waist circumference was associated with lower antibody (Ab) titres (R = -0.324, p = 0.004); smokers had lower levels compared to non-smokers [1099 (1350) vs. 1921 (1375), p = 0.007], as well as hypertensive versus normotensive [650 ± 1192 vs. 1911 (1364), p = 0.001] and dyslipideamic compared to those with normal serum lipids [534 (972) vs 1872 (1406), p = 0.005]. Multivariate analysis showed that higher waist circumference, smoking, hypertension, and longer time elapsed since second vaccine inoculation were associated with lower Ab titres, independent of BMI, age. and gender. CONCLUSIONS: Central obesity, hypertension, and smoking are associated with lower Ab titres following COVID-19 vaccination. Although it is currently impossible to determine whether lower SARS-CoV-2 Abs lead to higher likelihood of developing COVID-19, it is well-established that neutralizing antibodies correlate with protection against several viruses including SARS-CoV-2. Our findings, therefore, call for a vigilant approach, as subjects with central obesity, hypertension, and smoking could benefit from earlier vaccine boosters or different vaccine schedules.

Case Report: Pituitary Morphology and Function Are Preserved in Female Patients With Idiopathic Intracranial Hypertension Under Pharmacological Treatment.

Idiopathic Intracranial Hypertension is a neurological disorder primarily affecting overweight women of childbearing age. It is often characterized by radiologic evidence of empty sella (ES), which is in turn frequently associated with pituitary dysfunction, with the somatotropic axis most commonly affected. No recent evidence is available relative to the presence of pituitary hormone deficiencies in adult patients with Idiopathic Intracranial Hypertension (IIH) under pharmacological therapy. We therefore explored pituitary function and morphology in a small cohort of female patients with IIH treated with acetazolamide. Fifteen female patients aged 42 ± 13 years with IIH lasting between 12 and 18 months were evaluated. All patients were affected by recurrent headaches in addition to visual changes of variable severity. IIH diagnosis was made after exclusion of other causes of raised intracranial pressure, and a specific ophthalmological evaluation was conducted to assess for the presence of papilledema. No particular endocrinological disturbances were detected during the enrolment visits, except for a high obesity prevalence (87%, BMI 35.16 ± 8.21 kg/m2), one case of total thyroidectomy for papillary thyroid carcinoma and two patients with irregular menses and mild hirsutism. All the participants underwent a pituitary MRI with contrast, and two different operators performed pituitary measurements in coronal and sagittal scans for morphologic assessment. Blood samples for the anterior pituitary axis evaluation were collected, and the somatotropic axis was further evaluated with a GHRH + Arginine test; other dynamic tests were performed in case of suspected hormonal deficiency. Despite ES being found in 73% of the patients, pituitary volume was preserved, ranging from 213.85 to 642.27mm3 (389.20 ± 125.53mm3); mean coronal pituitary height was 4.53 ± 1.33 mm. Overall, baseline anterior pituitary hormones levels were within normal ranges, and none of the patients with ES had an altered response to the GHRH + arginine stimulation test. We found one patient suffering from iatrogenic hyperthyroidism and two diagnosed with subclinical primary hypothyroidism due to Hashimoto's thyroiditis. Two young patients were suspected of having polycystic ovary syndrome, and they were therefore further investigated. In conclusion, this case series shows that, despite the high prevalence of ES, the pituitary function of IIH patients treated with acetazolamide is preserved. To date, there is no evidence regarding the trend over time or upon treatment discontinuation in regard to the pituitary function of patients with IIH, and it is therefore not possible to infer whether our finding would be replicable in such settings. We therefore suggest an endocrine follow-up over time in order to monitor for potential pituitary dysfunction.